1. Field of the Invention
The present invention relates to thienopyridine compounds which are potassium channel inhibitors. Pharmaceutical compositions comprising the compounds and their use in the treatment or prevention of cancer, arrhythmias, autoimmune diseases and inflammatory diseases, including gastric cancer, atrial fibrillation, type-2 diabetes mellitus, rheumatoid arthritis, type-1 diabetes, inflammatory bowel disorder and demyelinating disorders such as multiple sclerosis are also provided.
2. Background Art
Ion channels are proteins that span the lipid bilayer of the cell membrane and provide an aqueous pathway through which specific ions such as Na+, K+, Ca2+ and Cl− can pass. Potassium channels represent the largest and most diverse sub-group of ion channels and they play a central role in regulating the membrane potential and controlling cellular excitability. Potassium channels have been categorized into gene families based on their amino acid sequence and their biophysical properties.
Compounds which modulate potassium channels have multiple therapeutic applications in several disease areas including cardiovascular, neuronal, auditory, renal, metabolic, immunosuppression and cell proliferation. More specifically potassium channels such as Kv4.3, Kir2.1, hERG, KvLQT1/MinK, IKACh, IKAdo, KATP and Kv1.5 are involved in the repolarisation phase of the action potential in cardiac myocytes. Furthermore channels such as Kv1.3 and IKCa1 are essential for maintaining the plasma membrane potential of numerous mammalian cells, including lymphocytes, the key effector cells of the adaptive immune system.
The human delayed rectifier voltage gated potassium channel subunit, Kv1.5, is exclusively expressed in atrial myocytes and is believed to offer therapeutic opportunities for the management of atrial fibrillation for several different reasons (see review, Brendel and Peukert, 2002): (i) There is evidence that Kv1.5 underlies the cardiac ultrarapid delayed rectifier (Kv(ur)) physiological current in humans due to similar biophysical and pharmacological properties. This has been supported with antisense oligonucleotides to Kv1.5 which have been shown to reduce Kv(ur) amplitude in human atrial myocytes. (ii) electrophysiological recordings have demonstrated that Kv(ur) is selectively expressed in atrial myocytes, and therefore avoids inducing potentially fatal ventricular arrhythmia through interfering with ventricular repolarisation. (iii) Inhibiting Kv(ur) in atrial fibrillation-type human atrial myocytes prolonged the action potential duration compared to normal healthy human atrial myocytes. (iv) Prolonging the action potential duration by selectively inhibiting Kv1.5 could present safer pharmacological interventions for protecting against atrial re-entrant arrhythmias such as atrial fibrillation and atrial flutter compared to traditional class III antiarrythmics, by prolonging the atrial refractory period while leaving ventricular refractoriness unaltered. Class III antiarrythmics have been widely reported as a preferred method for treating cardiac arrhythmias.
Drugs that maintain cardiac sinus rhythm long-term without proarrhythmic or other side effects are highly desirable and not currently available. Traditional and novel class III antiarrythmic potassium channel blockers have been reported to have a mechanism of action by directly modulating Kv1.5 or Kv(ur). The known class III antiarrythmics ambasilide (Feng et al., 1997), quinidine (Wang et al., 1995), clofilium (Malayev et al., 1995) and bertosamil (Godreau et al., 2002) have all been reported as potassium channel blockers of Kv(ur) in human atrial myocytes. The novel benzopyran derivative, NIP-142, blocks Kv1.5 channels, prolongs the atrial refractory period and terminates atrial fibrillation and flutter in in vivo canine models, and S9947 inhibited Kv1.5 stably expressed in both Xenopus oocytes and Chinese hamster ovary (CHO) cells and Kv(ur) in native rat and human cardiac myocytes. Elsewhere, other novel potassium channel modulators which target Kv1.5 or Kv(ur) have been described for the treatment of cardiac arrhythmias, these include biphenyls (Peukert et al, 2003), thiophene carboxylic acid amides (WO0248131), bisaryl derivatives (WO0244137, WO0246162), carbonamide derivatives (WO0100573, WO0125189) anthranillic acid amides (WO2002100825, WO02088073, WO02087568), dihydropyrimidines (WO0140231), cycloalkylamine derivatives (WO2005018635), isoquionolines (WO2005030791), quinolines (WO2005030792), imidazopyrazines (WO2005034837), benzopyranols (WO2005037780), isoquinolinones (WO2005046578), cycloakyl derivatives (WO03063797), indane derivatives (WO0146155 WO9804521), tetralin benzocycloheptane derivatives (WO9937607), thiazolidone and metathiazanone derivatives (WO9962891), benzamide derivatives (WO0025774), isoquinoline derivatives (WO0224655), pyridazinone derivatives (WO9818475 WO9818476), chroman derivatives (WO9804542), benzopyran derivatives (WO0121610, WO03000675, WO0121609, WO0125224, WO02064581), benzoxazine derivatives (WO0012492), and the novel compound A1998 purified from Ocean material (Xu & Xu, 2000).
The Kv1.3 channel is expressed in both white and brown adipose tissue, and skeletal muscle. Inhibition of the channel potentiates the hypoglycemic action of insulin, through increased insulin-stimulated glucose uptake in these tissues. This is supported by in vivo data, showing that Kv1.3 inhibition in mice with type 2 diabetes mellitus were significantly more sensitive to insulin. There is strong evidence that Kv1.3 inhibition improves peripheral glucose metabolism by facilitating GLUT4 translocation to the plasma membrane of adipocytes and myocytes (Desir, 2005). Small molecule inhibitors of Kv1.3 are emerging as potential targets in the management of type-2 diabetes, through their actions as insulin sensitisers (WO02-100248).
Voltage gated potassium channels are thought to be involved in the proliferation of many types of cells including tumour cells. The neoplastic process may involve the overexpression of the Kv channels and the related channel activity. Changes in potassium channel expression have been implicated in gastric cancer (Lan et al 2005) and chronic prostatitis (Liang et al 2005). Potassium channels have also been shown to be associated with the proliferation of endothelial cells possibly as they play a role in cell cycle regulation (Erdogan et al 2004).
Human T lymphocytes possess two types of potassium channels: the voltage-gated potassium Kv1.3 and the Ca2+-activated IKCa1 K+ channels. These channels set the resting membrane potential of T-lymphocytes, playing a crucial role in the Ca2+ signal transduction pathway that lead to activation of these cells following antigenic stimulation. Disruption of these pathways can attenuate or prevent the response of T-cells to antigenic challenge resulting in immune suppression.
The voltage-gated Kv1.3 and the Ca2+-activated IKCa1 K+ channels are expressed in T-cells in distinct patterns that accompany the proliferation, maturation and differentiation of these cells. The immunomodulatory effects of channel blockers depends on the expression levels of Kv1.3 and IKCa1 channels, which change dramatically when T-cells transition from resting to activated cells, and during differentiation from the naïve to the memory state. Kv1.3 channels dominate functionally in quiescent cells of all T-cell subtypes (naïve, TCM and TEM). Activation has diametrically opposite effects on channel expression; as naïve and TCM cells move from resting to proliferating blast cells, they upregulate IKCa1 channels. Consequently activated naïve and TCM cells express ˜500 IKCa1 channels and an approximately equivalent number of Kv1.3 channels. In contrast, activation of TEM cells enhances Kv1.3 expression without any change in IKCa1 levels. Functional Kv1.3 expression increases dramatically to 1500 Kv1.3 channels/cell, and their proliferation is sensitive to Kv1.3 blockers (Wulff et al., 2003). B-cells also show a switch in K+ channel during differentiation that parallels the changes seen in the T-cell lineage (Wulff et al., 2004). The discovery that the majority of myelin-reactive T-cells in patents with MS are Kv1.3high TEM cells has raised interest in the therapeutic potential of Kv1.3 blockers in autoimmune disorders. Kv1.3 blockers have been shown to ameliorate adoptive EAE induced by myelin-specific memory T-cells (a model for MS) and to prevent inflammatory bone resorption in experimental periodontal disease caused mainly by memory cells. In addition, there is increasing evidence implicating late memory cells in the pathogenesis of type-1 diabetes, rheumatoid arthritis, psoriasis, inflammatory bowel disorder, Crohn's disease, Grave's disease, Plummer's disease, systemic lupus erythematosus, chronic graft rejection and chronic graft-vs-host disease. Specific Kv1.3 blockers might therefore constitute a new class of memory-specific immunomodulators.
Numerous novel small molecule Kv1.3 channel blockers have been reported for the management of autoimmune disorders. These include the iminodihydroquinolines WIN173173 and CP339818 (Nguyen et al., 1996), the benzhydryl piperidine UK-78,282 (Hanson et al. 1999), correolide (Felix et al., 1999), cyclohexyl-substituted benzamide PAC (US-06194458, WO0025774), sulfamidebenzamidoindane (US-06083986), Khellinone (Baell et al., 2004), dichloropenylpyrazolopyrimidine (WO-00140231) and psoralens (Schmitz et al., 2005).
Thienopyridines have been reported to be useful as 5-HT receptor modulators and phosphatase and kinase inhibitors amongst others.
Thienopyridines substituted at the 2-position by alkyl, aryl, halogen, hydrogen or arylthioxy groups, the 4-position by alkyl, aryl, cyano, halogen and heteroaryl groups, in the 6-position by a secondary amide group and the 7-position by hydroxyl have been claimed as hypoxia inducible factor (HIF) modulators (WO2006094292).
Thienopyridines substituted at the 4-position by an amino group and at the 7-position by an aryl group have been claimed as inhibitors of kinases, in particular COT and MK2 kinases for the treatment of protein kinase-related diseases (WO2005110410).
Thienopyridines substituted at the 3-position by an alkyl or aryloxymethyl group, at the 4-position by an amino group and at the 7-position by a carboxamide, secondary amide or ester group have been claimed as KDR and FGFR kinase inhibitors for the treatment of cancer (US2005256154).
Thienopyridines substituted at the 2-position by an amide, carboxy or ester group, at the 3-position by an alkoxy group, at the 4-position by a hydrogen or halogen and at the 6-position by an alkyl substituent have been claimed as protein tyrosine phosphatase 1B inhibitors for treating diabetes and related diseases (WO2005081960).
Thienopyridines substituted at the 2-position by a hydrogen or alkyl group, at the 3-position by hydrogen, alkyl or heteroaryl groups, at the 4-position with an amino group and at the 7-position by hydrogen, halogen, aryl, heteroaryl, carboxy and secondary or tertiary amino groups have been claimed as tyrosine kinase inhibitors, useful for treating and preventing tumors and cancers (US2005043347, US2005026944, US2005020619, WO2004100947).
Thienopyridines substituted at the 2-position by an aryl group, at the 3-position by hydrogen or an alkyl group, at the 4-position by an amino group and at the 7-position by a carboxamide group have been claimed as IKKβ enzyme inhibitors for the treatment of inflammatory, immunoregulatory, metabolic, infectious and cell proliferative diseases or conditions (WO2005105809, US2004097485).
Thienopyridines substituted at the 2-position by a hydrogen or halogen group, 3-position by a halogen or sulfonamido group, 4-position by a piperazinyl group have been claimed as having inhibitory activities on 5-HT1A, 5-HT3 an 5-HT6 receptors, and are useful for the treatment of conditions relating to obesity, type-2 diabetes and CNS disorders (WO2005082887).
Thienopyridines substituted at the 2-position by hydrogen, 3-position by a heteroaryl group, 4-position by an amino group have been claimed as inhibitors of trypsin-like serine protease enzymes, and are useful as anticoagulant agents for treatment and prevention of thromboembolic disorders (WO0039108).
Thienopyridines substituted at the 2-position by an ester group, 3-position by an amino group and 4-position by an alkoxy group have been claimed as α1 adrenergic antagonists (U.S. Pat. No. 6,046,207).
Thienopyridines substituted at the 2-position by a hydrogen, halogen or cyano group, 3-position by a hydrogen or cyano group and at the 4-position by an oxypropanol derivative group have been claimed as useful adrenergic β-blocking agents, hypolidemics, hypoglycemics and antiarrhythmics (DE77-2703888, US75-605972, DE75-2536675).